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United States Patent |
5,681,855
|
Schutz
,   et al.
|
October 28, 1997
|
PGE.sub.1 emulsion composition kit
Abstract
The invention concerns a kit for the preparation of an emulsion containing
prostaglandin E.sub.1, a method of preparing the emulsion and a method of
preparing the emulsion composition contained in the kit. The emulsion
prepared using this kit is suitable for parenteral application.
Inventors:
|
Schutz; Andreas (Koln, DE);
Mika; Hans-Jurgen (Bonn, DE);
Sievert; Frank (Burscheid, DE)
|
Assignee:
|
Schwarz Pharma AG (DE)
|
Appl. No.:
|
535001 |
Filed:
|
September 21, 1995 |
PCT Filed:
|
March 19, 1994
|
PCT NO:
|
PCT/DE94/00325
|
371 Date:
|
September 21, 1995
|
102(e) Date:
|
September 21, 1995
|
PCT PUB.NO.:
|
WO94/21263 |
PCT PUB. Date:
|
September 29, 1994 |
Foreign Application Priority Data
| Mar 24, 1993[DE] | 43 09 579.8 |
Current U.S. Class: |
514/559; 514/23; 514/78; 514/529; 514/560; 514/573; 514/738; 514/937; 514/970 |
Intern'l Class: |
A61K 031/19 |
Field of Search: |
514/559,560,23,78,529,573,738,937,970
|
References Cited
U.S. Patent Documents
4684633 | Aug., 1987 | Imagawa et al. | 514/78.
|
Foreign Patent Documents |
0 150 732 A2 | Aug., 1985 | EP.
| |
0 161 445 A1 | Nov., 1985 | EP.
| |
0 331 755 A1 | Sep., 1989 | EP.
| |
28 18 655 A1 | Nov., 1978 | DE.
| |
41 25 255 A1 | Feb., 1993 | DE.
| |
53-148 518 A | ., 0000 | JP.
| |
57-156 460 A | ., 0000 | JP.
| |
61-100 518 A | ., 0000 | JP.
| |
A 05043450 | Feb., 1993 | JP.
| |
WO 91/11172 | Aug., 1991 | WO.
| |
Other References
The United States Pharmacopeia, The National Formulary, USP 23, NF 18,
1995, pp. 2241, 2269.
|
Primary Examiner: Cook; Rebecca
Attorney, Agent or Firm: Merchant, Gould, Smith, Edell, Welter & Schmidt, P.A.
Claims
We claim:
1. A kit for the parenteral administration of prostaglandin E.sub.1
(PGE.sub.1) comprising
a) an anhydrous, lyophilized PGE.sub.1 emulsion composition, comprising:
at least one cryoprotection agent:
a polar fat which is an acetylated monoglyceride
a phospholipid; and
a hydrophilic emulsifier;
b) an aqueous dispersion medium, and
c) a filter.
2. The kit of claim 1 wherein the phospholipid is a glycerol phosphatide,
and the hydrophilic emulsifier is a polyoxyethylene polyoxypropylene
polymer.
3. The kit of claim 1, wherein the polar fat is a diacetylated
monoglyceride; the phospholipid is phosphatidylcholine, and the
hydrophilic emulsifier is poloxamer 188.
4. The kit of claim 1, wherein at least one fat and at least one emulsifier
are present in a ratio of about 1:2 to 10:1 by weight.
5. The kit of claims 1, wherein the phospholipid and the hydrophilic
emulsifier are present in a ratio of about 3:1 to 1:2 by weight.
6. The kit of claim 1, wherein the cryoprotection agent is at least one
member selected from the group consisting of a physiologically tolerated
mono-, di- or oligosaccharide and a sugar alcohol, or a mixture thereof.
7. The kit of claim 6, wherein the saccharide is at least one member
selected from the group consisting of trehalose and lactose, and the sugar
alcohol is at least one member selected from the group consisting of
sorbitol and mannitol.
8. The kit of claim 1, wherein the filter is a membrane filter with a pore
size of about 0.5-1.3 .mu.m, or a corresponding deep-bed filter.
9. The kit of claim 1, wherein the emulsion composition further comprises
at least one antioxidant, a physiologically tolerated salt thereof, a
physiologically tolerated buffer salt or a mixture thereof.
10. The kit of claim 9 wherein the antioxidant is .alpha.,.beta., .gamma.
or .delta.-tocopherol or a physiologically tolerated salt thereof.
11. The kit of claim 10, wherein the physiologically tolerated salt is a
phosphate, succinate, or acetate.
12. The kit of claim 1, wherein the internal, disperse phase of the
emulsion has an average particle diameter of about 0.1 .mu.m to 5 .mu.m.
Description
DESCRIPTION
The present invention relates to a kit for the preparation of a fat
emulsion which contains prostaglandin E.sub.1 (PGE.sub.1) for direct
parenteral use.
In particular, the invention relates to a kit consisting of
a) an anhydrous, lyophilized PGE.sub.1 -containing emulsion composition
b) an aqueous dispersion medium and
c) a filter
for the preparation of a PGE.sub.1 -containing fat emulsion, which is ready
for administration, by mixing, and extruding through the filter c), the
anhydrous, lyophilized PGE.sub.1 -containing emulsion composition a) with
the aqueous dispersion medium b).
PGE.sub.1 is a highly active tissue hormone which is successfully used, for
example, for the treatment of arterial occlusive disease. Used for this
purpose is a PGE.sub.1 -.alpha.-cyclodextrin complex which, dissolved in
physiological saline solution, is infused parenterally, preferably
intraarterially, as close as possible to the body region to be treated.
However, high pressure conditions and small dilution effects during the
intraarterial infusion make high demands on the equipment and the training
of the treating physician. Although intravenous infusion is simpler to
perform by comparison, even in this case infusion is possible only slowly
and in relatively high dilution because of the local irritant effect of
PGE.sub.1. Overall, the extended residence time of the active substance in
the vascular system before reaching the target site and, in particular,
the additional passage through the pulmonary circulation leads to
increased degradation of active substance. Both intraarterial and
intravenous infusions make high demands on the equipment and careful
adjustment of the infusion rate and are therefore usually performed in
hospital and not by the established physician, which impedes wide use of
the valuable active substance in the therapy of arterial occlusive
disease.
Fat emulsions are disperse systems in which the internal, disperse phase
consists of very fine fat particles which are homogeneously dispersed in
the external, continuous phase composed of water.
As a predominantly lipophilic substance, PGE.sub.1 can be partly or
completely incorporated into the internal phase of fat emulsions, from
which it is then released in a delayed manner. This avoids high local
concentrations, degradation of the active substance is reduced and the
duration of action is increased so that incorporation into fat emulsions
is suitable for overcoming the problems described.
PGE.sub.1 -containing fat emulsions for parenteral use can be prepared by
dissolving PGE.sub.1 in the oil phase which is subsequently processed
further in accordance with a customary preparation process to give a fat
emulsion. This can take place, for example, by the heated oil and water
phases initially being roughly preemulsified with a mixer and then
microfine emulsification being carried out with a high-pressure
homogenizer, and the resulting fat emulsion subsequently being sterilized
with superheated steam. Microfine emulsification is necessary in order to
avoid changes in blood pressure and the risk of embolism as a consequence
of large fat particles. Although such PGE.sub.1 -containing fat emulsions
are suitable for solving the described disadvantages of the conventional
use of PGE.sub.1, their storage stability is low as a consequence of
hydrolytic degradation of the active substance, which impedes their
general utilizability.
According to U.S. Pat. No. 4,684,633, a fat emulsion which contains
prostaglandins and consists of vegetable oils, phospholipids and water can
be stabilized by using phospholipids which have been freed of
phosphatidylethanolamine. However, stabilization of the active substance
is shown only for the condition of brief sterilization at 125.degree. C.
for 2.2 min. Data on the stability on long-term storage are lacking. The
formulation also contains water so that degradation of active substance as
a consequence of hydrolysis cannot be ruled out in principle.
Besides stabilization of the active substance in a fat emulsion ready for
administration, fat emulsions containing intact active substance can also
be used by preparing them only immediately before use. One example of this
is given in EP 0 331 755, consisting of active substance, saccharides
and/or amino, acids, which are combined and vigorously mixed immediately
before use. Vigorous mixing is absolutely necessary in order to make it
possible to disperse the active substance in the fat emulsion. However,
long mixing times are disadvantageous on use.
An example relating to prostaglandins which is mentioned in EP 0 331 755,
Example 3, describes an active substance composition consisting of a
prostaglandin and triethanolamine. However, triethanolamine is not without
objections physiologically so that its use in pharmaceutical formulations,
especially in injectable products, should be avoided where possible.
Thus there continued to be A need for a possibility, which can be handled
simply and rapidly, for using a PGE.sub.1 -containing fat emulsion. It
ought fundamentally to preclude hydrolysis of the active substance during
storage owing to absence of water, use only physiologically acceptable
auxiliary substances and avoid long preparation and equilibration times
before use.
It has been possible to close this gap in the state of the art by making
available a kit for a PGE.sub.1 -containing emulsion which can be used and
consists of
a) an anhydrous, lyophilized PGE.sub.1 -containing emulsion composition
b) an aqueous dispersion medium and
c) a filter.
In this case PGE.sub.1 is contained in an anhydrous emulsion composition so
that degradation of active substance as a consequence of hydrolysis is
fundamentally ruled out, and dispersion in the fat phase of the emulsion
is ensured from the outset.
The PGE.sub.1 -containing emulsion composition contained in the kit
advantageously contains at least one cryoprotection agent and/or at least
one bulking agent, a polar fat, a phospholipid and/or a hydrophilic
emulsifier. Polar fats are glycerides whose hydroxyl groups, besides
higher fatty acids, are also esterified with short-chain carboxylic acids
or are unesterified in free form and, in contrast to triglycerides with
higher fatty acids, have a certain affinity for polar solvents.
Hydrophilic emulsifiers are surfactants whose emulsifying behaviour is
crucially determined by their hydrophilic groups and preferentially form
fat-in-water emulsions.
The PGE.sub.1 -containing emulsion composition contained in the kit
preferably contains acetylated monoglycerides, glycerol phosphatides
and/or polyoxyethylene polyoxypropylene polymers.
The anhydrous PGE.sub.1 -containing emulsion composition contained in the
kit particularly preferably contains diacetylated monoglycerides,
phosphatidylcholine and/or poloxamer 188.
According to an expedient embodiment, the fat component(s) and the
emulsifier(s) are present in a ratio of 1:2 to 10:1 by weight, preferably
in a ratio of 3:2 by weight.
According to another expedient embodiment, the phospholipid and the
hydrophilic emulsifier are present in a ratio of 3:1 to 1:2 by weight,
preferably in a ratio of 3: 2 by weight.
According to an advantageous embodiment, the anhydrous PGE.sub.1
-containing emulsion composition contained in the kit contains as
cryoprotection agents/bulking agents physiologically tolerated mono-, di-
or oligosaccharides, especially trehalose and lactose and/or sugar
alcohols such as sorbitol or mannitol.
According to a particularly expedient embodiment, the kit for a PGE.sub.1
-containing emulsion which can be used contains a filter which is a
membrane filter with a pore size of 0.5-1.3 .mu.m, preferably 0.8 .mu.m,
or a corresponding deep-bed filter. Preferred in this connection are
commercially available devices in which the filter is firmly integrated
between cannula and fit-on connector.
According to a preferred embodiment, the anhydrous PGE.sub.1 -containing
emulsion composition contained in the kit contains at least one
conventional antioxidant, in particular from the group of tocopherols such
as .alpha.-, .beta.-, .gamma.- or .delta.-tocopherol, preferably
.alpha.-tocopherol, and physiologically tolerated salts thereof, such as
phosphates, succinates and acetates and/or physiologically tolerated
buffer salts.
According to a particularly preferred embodiment, the internal phase of the
emulsion which can be used and is prepared with the kit has an average
particle diameter of 0.1 .mu.m to 5 .mu.m, preferably 0.5 .mu.m to 2.0
.mu.m.
The emulsion composition contained in the kit according to the invention
can be prepared by removing the aqueous phase by lyophilization from an
emulsion which has been prepared by the processes and technologies
customary in the production of pharmaceuticals.
The invention therefore also relates to a process for the preparation of
the anhydrous PGE.sub.1 -containing emulsion composition contained in the
kit according to the invention, which is characterized in that an emulsion
containing an active substance is prepared in a conventional way and its
external, aqueous phase is subsequently removed by freeze-drying.
It is possible with the kit according to the invention to prepare in a
simple manner a PGE.sub.1 -containing emulsion which can be used, i.e. is
suitable for direct parenteral administration.
It therefore furthermore relates to a process for the preparation of a
PGE.sub.1 -containing emulsion, which can be used, by means of the kit
according to the invention, which is characterized in that the hydrous
PGE.sub.1 -containing emulsion composition a) is mixed with the aqueous
dispersion medium b) and extruded through the filter c).
EXAMPLE
2.8 g of poloxamer 188 and 40.0 g of trehalose were dissolved by heating in
320 g of water for injections. Subsequently 4.00 g of phosphatidyldholine,
13.0 g of diacetylated monoglycerides, 0.20 g of .alpha.-tocopherol were
dissolved in 20.0 g of absolute ethanol with gentle heating and under an
inert atmosphere.
The aqueous phase was transferred into a suitable presterilized reaction
vessel (IKA LR-A 1000 laboratory reactor, Jahnke & Kunkel GmbH, Staufen,
Germany) with temperature-control device, stirrer tool and toothed rim
disperser (Ultraturrax, Jahnke & Kunkel .mu.mbH, Staufen, Germany) and
heated to 80.degree. C. while stirring under a vacuum of<1 mbar. While
maintaining the vacuum and the stirring, the ethanolic emulsifier lipid
phase was injected directly into the aqueous phase with vigorous
homogenization using the Ultraturrax. The mixture was subsequently cooled,
with continuous stirring and maintenance of the vacuum, to room
temperature while vigorous homogenization was carried out using the
toothed rim dispersing rod for about 1 min in several periods. To
incorporate the active substance, 131.6 mg of PGE.sub.1
-.alpha.-cyclodextrin complex were added to the cooled emulsion. The
resulting emulsion containing active substance was sterilized by
filtration and transferred under aseptic conditions using a Dispensette
with a capacity of 2 ml per single dose to a height of about 1 cm into
presterilized vials. After charging, the vials were provided with
stoppers, placed in the lyophilizer and frozen at -50.degree. C. for 5
hours. The subsequent lyophilization process was carried out as shown in
the following table:
______________________________________
Time Temperature
Pressure
(hours) (.degree.C.)
(.mu.bar)
______________________________________
24 -30 100
10 20 1
______________________________________
Subsequently the vacuum was removed with simultaneous introduction of
nitrogen, the vials were closed by hydraulic lowering of the stoppers and
were removed from the lyophilizer under aseptic conditions after it had
been opened.
After addition of water, the product cakes contained in them disintegrated
spontaneously to give a homogeneous emulsion. This was removed using a
syringe through a membrane filter which was located between the latter and
the cannula and had a pore size of 0.8 pro, and was investigated for its
particle sizes (volume distribution) (method: laser light scattering;
Malvern Master Sizer, Series 3.01, Malvern Instruments Ltd., Spring Lane,
South Malvern, Worcestershire, WR14 1AQ, UK).
The measurement showed that 99.9% of all the particles are<4.10 .mu.m, no
particle is>5.64 .mu.m and the average particle size is 1.15 .mu.m. The
present emulsion thus has a particle size distribution suitable for
parenteral administration.
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